Head and neck cancer (HNC) continues to be a major cause of death and disfigurement, and therapies for HNC have not improved significantly in the last several decades. There is now convincing evidence that a subset of HNC, particularly those from the oropharyngeal (tonsillar) region, are caused by human papillomavirus (HPV). Over 50% of oropharyngeal cancers contain and express the E6/E7 genes from HPV, mostly HPV-16, a subtype that is frequently involved in the development of cervical cancer. Our studies have demonstrated that HPV-16 E6/E7 can immortalize and transform human and mouse tonsillar epithelial cells. While it has been demonstrated that inhibition of HPV genes in cancer cell lines can effectively suppress transformation in vitro, current strategies of inhibition are relatively non-specific and inefficient for in vivo delivery. We have developed a unique mouse model of HNC in which HPV-16 E6/E7 mouse tonsillar epithelial cells (MTECs) are transformed to tumorigenicity by expression of mutant Ras or ErbB2. This unique HNC model systemwill allow the assessment of methods to inhibit HPV genes to suppress tumorigenic growth in a syngeneic immunocompetent host. Our group has previously shown that chimeric all RNA aptamer-siRNAs can be utilized in vivo for specific binding, internalization, and delivery of siRNAs into target cells. Here, we propose to develop RNA aptamers that specifically localize and internalize into HPV transformed MTECs. Aptamer-siRNA chimeras that target HPV genes will then be tested for their ability to specifically inhibit growth of HPV transformed tonsillar epithelial cells in vitro and in vivo. Overall, our proposed proof-of-concept studies could lead to the development of more specific and effective methods to treat HPV associated oropharyngeal cancer and other oral diseases. PUBLIC HEALTH RELEVANCE: The development of novel methodologies to specifically and efficiently inhibit HPV genes in transformed tonsillar epithelial cells could lead to advanced treatment methods for head and neck cancer. The findings from this work could be applicable to the treatment of other oral diseases, as well.